Using a Systematic Approach to Select Critical Process Parameters

Harmonized regulations call for a risk-based and systematic approach to evaluating and selecting CPPs for accurate process control. Critical process parameters (CPPs) and their associated process controls are crucial to drug development and process validation and to the evaluation of every manufacturing unit operation.

The systematic approach for CPP selection and use discussed in this article was developed in line with the International Conference of Harmonization (ICH) Q8, Q9, Q10, and Q11 guidelines, which recommend quality risk management and the identification of CPPs as part of drug quality and process control development (1–4).

Specifically, ICH Q8(R2) Section 2.5 on Control Strategy (1), states:

"…. These controls should be based on product, formulation and process understanding and should include, at a minimum, control of the critical process parameters and material attributes…. A comprehensive pharmaceutical development approach will generate process and product understanding and identify sources of variability. Sources of variability that can impact product quality should be identified, appropriately understood, and subsequently controlled. Understanding sources of variability and their impact on downstream processes or processing, in-process materials, and drug product quality can provide an opportunity to shift controls upstream and minimize the need for end product testing. Product and process understanding, in combination with quality risk management (see ICH Q9), will support the control of the process such that the variability (e.g., of raw materials) can be compensated for in an adaptable manner to deliver consistent product quality."

CPP selection has traditionally been difficult because of a lack of a systematic approach to the problem. CPPs can be found in media, upstream and downstream unit operations, and drug-product processing. Due to the large number of unit operations and media complexity, it is easy to overlook processing parameters and materials that may impact drug-substance and drug-product variation and CQAs. Failure to identify critical parameters can result in unexplainable variation during batch processing and lot acceptance.

Selecting CPPs

The key steps to selecting CPPs and their application to process control are as follows:

Explore the design space for all key factors identified during the risk assessment using design of experiments (DOE) or other multivariate methods

Determine the factor effect size and select all CPPs

Evaluate CPPs for ease of control and practical application to process control.

These steps are considered in detail below.

CQA identification. CQAs are those attributes that are important to the quality of the drug product and that remain consistent with those used in clinical studies. The industry generally associates them with ICH parameters, such as identity, purity, potency, stability, and safety. CQAs provide the justification and rationale of what is critical to function and what ultimately needs to be controlled to assure compliance and fit for use. CQAs are the foundation upon which the CPPs must be associated. Line-of-site between CPPs and CQAs is considered a major component of the drug-development strategy.

Ingredient, materials, and container closure. Key parameters and analytical methods that measure the attributes of the API, excipients, key materials, and packaging/container closure must be examined using a quality risk-management (QRM) approach. This approach focuses on finding those attributes that will be crucial to maintaining the quality and stability of the drug substance and drug product. Key findings of this review will be added to the list of candidate process parameters that need to be controlled. Output of a QRM material assessment can help to generate candidate CPPs.

Unit operation process definition. Identification of all unit operations and their associated equipment sets and equipment capabilities in upstream and downstream processes are crucial when selecting those parameters that need to be controlled to assure potency and drug lot consistency. Small changes in time, temperature, pH, and other variables may result in changes to API characteristic, yield, and impurity profiles. Output of a QRM unit operation assessment will generate some candidate CPPs. Because biologics are extremely sensitive to processing, it is important that each unit operation is carefully evaluated for possible impacts to the large molecule and impurities.